Polyhydroxylated piperidines and their synthetic analogues have attracted a great deal of attention in recent years due to their ability to mimic sugars, and competitively and selectively inhibit glycosidases and glycosyltransferases, the carbohydrate processing enzymes. These attributes make hydroxylated piperidines (azasugars) likely therapeutic agents for the treatment of diseases related to metabolic disorders involving carbohydrates such as diabetes, cancer, AIDS, and viral infections, where glycoprotein processing is crucial. Recently three fagomine and some of its isomers were found from Xanthocercis zambesiaca occurring in southern Africa in dry forest. Among them, fagomine and 3-epi-fagomine have been shown to have activity against mammalian α-glucosidase and β-galactosidase. More recently fagomine was found to have a potent antihyperglycaemic effect in streptozocin-induced diabetic mice and a potentiation of glucose-induced insulin secretion.

Glycals, carbohydrates incorporating a double bond between C-1 and C-2, have emerged as powerful building blocks in synthetic chemistry especially in the context of oligosaccharide assembly. In light of this fact, it is perhaps surprising that the synthesis and chemistry of imino glycals, glycals in which the ring oxygen atom is replaced by nitrogen, has not been explored in a systematic fashion. Such compounds should participate in a diverse range of reactions (e.g. addition and cycloadditions reactions, metal catalyzed cross-couplings), and thus provide access to many potentially useful classes of imino sugars which are of interest because of their ability to influence a variety of biological processes by the inhibition of the glycosidase enzymes. Furthermore, imino glycals might serve as precursors to various glycosyl donors which could be used to make oligosaccharides incorporating nitrogen atoms, another area of current interest.
Article titled “Stereoselective synthesis and biological evaluation of D-fagomine, D-3-epi-fagomine and D-3,4-epi-fagomine analogs from D-glyceraldehyde acetonide as a common building block” by JA Díez et al. Published in Org Biomol Chem., 2012; 10(46), pp 9278-86 reports synthesis involves diastereoselective anti-vinylation of its homoallylimine, ring-closing metathesis, and stereoselective epoxidation followed by regioselective ring-opening or stereoselective dihydroxylation.
Article titled “Efficient and stereodivergent syntheses of D- and L-fagomines and their analogues” by N Kumari et al. published in European Journal of Organic Chemistry, 2009, 2009 (1), pp 160-169 reports the synthesis of d- and 1-fagomines 1, 4, 5 and 6 and their isomers from starting d-glycals. The syntheses involve elaboration of common amino alcohol precursors obtained from 2-deoxy-1-amino sugar derivatives. The key steps in the synthesis are intramolecular reductive amination and intramolecular N-heterocyclization.
Article titled “A divergent synthesis of 4-epi-fagomine, 3, 4-dihydroxypipecolic acid, and a dihydroxyindolizidine and their beta-galactosidase inhibitory and immunomodulatory activities” by KS Kumar et al. published in J Org Chem., 2013, 78(15), pp 7406-13 reports a divergent asymmetric synthesis of the iminosugars starting from a chiral homoallyl alcohol as the versatile intermediate. The homoallyl alcohol is prepared by a highly diastereoselective Barbier reaction on a D-glucose-derived aldehyde. The protection of hydroxyl function followed by reductive ozonolysis of the olefin and a subsequent one-pot three-step protocol involving a Staudinger reaction, reductive amination, and benzyloxy carbonyl protection yielded an important bicyclic furanopiperidine derivative.
Article titled “A synthesis of 2-epi-fagomine using gold (I)-catalyzed allene cyclisation” by Bates et al. published in a synthesis of 2-epi-fagomine via a highly stereoselective gold(I)-catalyzed allene cyclisation. A highly stereoselective Au(I)-catalyzed cyclization of allene (IV) is the key step in the synthesis of 2-epi-fagomine (VI).
Article titled “General synthesis and biological evaluation of alpha-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-alpha-C-glycosides)” by JY Goujon et al. published in Bioorg Med Chem., 2005, 13(6), pp 2313-24 reports a general synthesis of alpha-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-alpha-C-glycosides) by ring-opening reactions of an aziridine with various heteroatomic nucleophiles, including thiol, amine, alcohol, carboxylate and phosphate. This nine-step reaction sequence proceeded in an overall yield of 14-28% from tri-O-benzyl-D-glucal.
Article titled “Chemistry of imino glycals: preparation and application to the synthesis of (+)-fagomine” by J Desire et al. published in Synlett, 2001, 2001 (8), 1329-1331 reports the synthesis of imino glucal from tri-O-benzyl-D-glucal in 8 steps. This novel imino sugar building block is further converted into (+)-fagomine by a two-step hydrogenation sequence.
The prior art processes had many drawbacks such as poor yield and longer reaction sequence. Therefore there is need in the art to develop a shorter process for the preparation of piperidine alkaloids selected from (+)-fagomine, 4-epi-fagomine and nojirimycin with better yield.